Non-allergic rhinitis (“NAR”) affects millions of Americans, but the mechanism(s) remains unknown. Transient receptor potential vanilloid-1 (“TRPV1”) may be involved, as single dose studies of intranasal capsaicin, a TRPV1 agonist, have demonstrated reduced nasal congestion in rhinitis subjects.
Chronic rhinitis is defined as persistent inflammation of the mucosal membranes lining the nasal cavity, characterized by symptoms of nasal congestion, rhinorrhea, sneezing and itching with or without post-nasal drainage. (Settipane R A, Lieberman P. Update on nonallergic rhinitis. Ann Allergy Asthma Immunol 2001; 86:494-507; quiz-8. Wallace D V, Dykewicz M S, Bernstein D I, Blessing-Moore J, Cox L, Khan D A, et al. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol 2008; 122:S1-84.) A diagnosis requires the exclusion of structural abnormalities and underlying medical conditions that can manifest with rhinitis symptoms. (Settipane R A, Lieberman P. Update on nonallergic rhinitis. Ann Allergy Asthma Immunol 2001; 86:494-507; quiz-8. Wallace D V, Dykewicz M S, Bernstein D I, Blessing-Moore J, Cox L, Khan D A, et al. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol 2008; 122:S1-84.) Broadly defined, rhinitis can be divided into inflammatory and non-inflammatory rhinitis. (Wallace D V, Dykewicz M S, Bernstein D I, Blessing-Moore J, Cox L, Khan D A, et al. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol 2008; 122:S1-84. Bernstein J A. Characteristics of Non-Allergic Rhintiis. World Allergy Journal 2009; 2:102-5.)
Inflammatory rhinitis includes seasonal or perennial allergic rhinitis, entopic rhinitis and non-allergic rhinitis eosinophilic syndrome (“NARES”) whereas non-inflammatory rhinitis includes vasomotor rhinitis (“VMR”), commonly referred to as idiopathic rhinitis, and other non-allergic rhinitis conditions such as rhinitis medicamentosa, gustatory rhinitis and hormonally-induced rhinitis. (Bernstein J A. Characteristics of Non-Allergic Rhintiis. World Allergy Journal 2009; 2:102-5. Kaliner M. Classification of Nonallergic Rhinitis Syndromes With a Focus on Vasomotor Rhinitis, Proposed to be known henceforth as Nonallergic Rhinopathy. World Allergy Journal 2009; 2:98-101.) Since patients with allergic rhinitis often exhibit significant symptoms in response to irritant triggers, clinicians have postulated that allergic and non-allergic rhinitis components often co-exist and have therefore referred to this condition as “mixed rhinitis” (“MR”). (Bernstein J A, Rezvani, M. Mixed Rhinitis: A New Subclass of Chronic Rhinitis. in: Kaliner M, ed. Current Review of Rhinitis, 2nd ed 2006; Philadelphia, Pa.: 69-78.) Cross-sectional questionnaire survey studies have estimated that up to 75% of chronic rhinitis patients have either non-allergic or mixed rhinitis. (Settipane R A. Demographics and epidemiology of allergic and nonallergic rhinitis. Allergy Asthma Proc 2001; 22:185-9.)
Currently non-allergic rhinitis (“NAR”) conditions are diagnoses by exclusion, as the mechanism(s) of this disorder is unknown and therefore, there are no specific biomarkers or tests that establish a definitive diagnosis. (Bernstein J A. Characteristics of Non-Allergic Rhintiis. World Allergy Journal 2009; 2:102-5. Kaliner M. Classification of Nonallergic Rhinitis Syndromes With a Focus on Vasomotor Rhinitis, Proposed to be known henceforth as Nonallergic Rhinopathy. World Allergy Journal 2009; 2:98-101. Brandt D, Bernstein J A. Questionnaire evaluation and risk factor identification for nonallergic vasomotor rhinitis. Ann Allergy Asthma Immunol 2006; 96:526-32. Garay R. Mechanisms of vasomotor rhinitis. Allergy 2004; 59 Suppl 76:4-9; discussion-10.) The most popular mechanism postulated for non-allergic rhinitis has been an autonomic imbalance between the sympathetic and parasympathetic nervous system resulting in parasympathetic hyperactivity leading to nasal congestion and drainage. (Baraniuk J N. Sensory, parasympathetic, and sympathetic neural influences in the nasal mucosa. J Allergy Clin Immunol 1992; 90:1045-50. Jones A S. Autonomic reflexes and non-allergic rhinitis. Allergy 1997; 52:14-9.) Recently, transient receptor protein (“TRP”) ion channel activation leading to trigeminal nerve depolarization has been postulated to play an important role in NAR, as these ubiquitous receptors can be activated by different temperatures, chemicals, osmolality and other physical stimuli that are well recognized triggers of symptoms in NAR patients. (Bernstein J A. Characteristics of Non-Allergic Rhintiis. World Allergy Journal 2009; 2:102-5. Brandt D, Bernstein J A. Questionnaire evaluation and risk factor identification for nonallergic vasomotor rhinitis. Ann Allergy Asthma Immunol 2006; 96:526-32. Seki N, Shirasaki H, Kikuchi M, Sakamoto T, Watanabe N, Himi T. Expression and localization of TRPV1 in human nasal mucosa. Rhinology 2006; 44:128-34.)
Because mechanisms of NAR are poorly elucidated, there are still only a few medications approved for the treatment of this condition. Although clinical studies have found that the intranasal antihistamines, azelastine and olopatidine, intranasal ipratropium bromide and intranasal corticosteroids are relatively effective in relieving symptoms related to NAR, it is unclear how they are mechanistically exerting their effect. (Banov C H, Lieberman P. Efficacy of azelastine nasal spray in the treatment of vasomotor (perennial nonallergic) rhinitis. Ann Allergy Asthma Immunol 2001; 86:28-35. Georgitis J W, Banov C, Boggs P B, Dockhorn R, Grossman J, Tinkelman D, et al. Ipratropium bromide nasal spray in non-allergic rhinitis: efficacy, nasal cytological response and patient evaluation on quality of life. Clin Exp Allergy 1994; 24:1049-55. Lieberman P L, Settipane R A. Azelastine nasal spray: a review of pharmacology and clinical efficacy in allergic and nonallergic rhinitis. Allergy Asthma Proc 2003; 24:95-105. Scadding G K, Lund V J, Jacques L A, Richards D H. A placebo-controlled study of fluticasone propionate aqueous nasal spray and beclomethasone dipropionate in perennial rhinitis: efficacy in allergic and non-allergic perennial rhinitis. Clin Exp Allergy 1995; 25:737-43. Ciprandi G. Treatment of nonallergic perennial rhinitis. Allergy 2004; 59 Suppl 76:16-22; discussion-3.)
Capsaicin is a pungent substance found in capsicum spp. (red pepper) that is known to ablate sensory nerve fibers in NAR patients leading investigators to postulate a role for afferent C-fibers in NAR. (Blom H M, Van Rijswijk J B, Garrelds I M, Mulder P G, Timmermans T, Gerth van Wijk R. Intranasal capsaicin is efficacious in non-allergic, non-infectious perennial rhinitis. A placebo-controlled study. Clin Exp Allergy 1997; 27:796-801.) This observation was supported by early placebo controlled studies that treated NAR patients with topical capsaicin and found significant improvement in symptom scores compared to placebo without changes in levels of mast cell mediators (i.e., leukotrienes, prostaglandin (PGD2) or tryptase) indicating that the effect of this medication was not due to reduction in mast-cell mediated inflammation. (Blom H M, Van Rijswijk J B, Garrelds I M, Mulder P G, Timmermans T, Gerth van Wijk R. Intranasal capsaicin is efficacious in non-allergic, non-infectious perennial rhinitis. A placebo-controlled study. Clin Exp Allergy 1997; 27:796-801. Blom H M, Severijnen L A, Van Rijswijk J B, Mulder P G, Van Wijk R G, Fokkens W J. The long-term effects of capsaicin aqueous spray on the nasal mucosa. Clin Exp Allergy 1998; 28:1351-8.)
Subsequently, it was discovered that capsaicin exerted its activity through activation of the TRP vanilloid-1 (“TRPV1”) ion channel which leads to desensitization of nasal sensory neural fibers and reduction in nasal hyperresponsiveness. (Seki N, Shirasaki H, Kikuchi M, Sakamoto T, Watanabe N, Himi T. Expression and localization of TRPV1 in human nasal mucosa. Rhinology 2006; 44:128-34.) Single intermittent short term dosing studies with intranasal capsaicin in AR and NAR have confirmed that intranasal capsaicin is effective at reducing nasal congestion and discharge. (Blom H M, Van Rijswijk J B, Garrelds I M, Mulder P G, Timmermans T, Gerth van Wijk R. Intranasal capsaicin is efficacious in non-allergic, non-infectious perennial rhinitis. A placebo-controlled study. Clin Exp Allergy 1997; 27:796-801. Blom H M, Severijnen L A, Van Rijswijk J B, Mulder P G, Van Wijk R G, Fokkens W J. The long-term effects of capsaicin aqueous spray on the nasal mucosa. Clin Exp Allergy 1998; 28:1351-8. Lacroix J S, Buvelot J M, Polla B S, Lundberg J M. Improvement of symptoms of non-allergic chronic rhinitis by local treatment with capsaicin. Clin Exp Allergy 1991; 21:595-600. Sanico A M, Philip G, Proud D, Naclerio R M, Togias A. Comparison of nasal mucosal responsiveness to neuronal stimulation in non-allergic and allergic rhinitis: effects of capsaicin nasal challenge. Clin Exp Allergy 1998; 28:92-100. Van Rijswijk J B, Boeke E L, Keizer J M, Mulder P G, Blom H M, Fokkens W J. Intranasal capsaicin reduces nasal hyperreactivity in idiopathic rhinitis: a double-blind randomized application regimen study. Allergy 2003; 58:754-61.)
However, the concentration of capsaicin used and found effective in these studies, ranging from 30 ppm to 300 ppm, was very irritating and required a physician to co-administer a local anesthetic making it impractical and intolerable for patients to self-administer the composition or use this treatment long term. (Blom H M, Van Rijswijk J B, Garrelds I M, Mulder P G, Timmermans T, Gerth van Wijk R. Intranasal capsaicin is efficacious in non-allergic, non-infectious perennial rhinitis. A placebo-controlled study. Clin Exp Allergy 1997; 27:796-801. Blom H M, Severijnen L A, Van Rijswijk J B, Mulder P G, Van Wijk R G, Fokkens W J. The long-term effects of capsaicin aqueous spray on the nasal mucosa. Clin Exp Allergy 1998; 28:1351-8. Lacroix J S, Buvelot J M, Polla B S, Lundberg J M. Improvement of symptoms of non-allergic chronic rhinitis by local treatment with capsaicin. Clin Exp Allergy 1991; 21:595-600. Van Rijswijk J B, Boeke E L, Keizer J M, Mulder P G, Blom H M, Fokkens W J. Intranasal capsaicin reduces nasal hyperreactivity in idiopathic rhinitis: a double-blind randomized application regimen study. Allergy 2003; 58:754-61.) Applicant is not aware of any prior studies disclosing, teaching or suggesting a composition comprising capsicum/capsaicin present in an effective concentration, that may be self-administered as a mono-therapy by the user. Furthermore, Applicant is not aware of any studies demonstrating clinical efficacy of capsicum/capsaicin at concentrations 10% or less of the dosages used in previous rhinitis clinical trials. What is needed in the industry is a composition comprising capsicum/capsaicin that may be administered intranasally in an effective concentration, allowing the user to self-administer the composition without the need for the user to visit a physician's office for each treatment.
According to an embodiment of the present invention, it has been unexpectedly discovered that certain concentrations of capsicum comprising capsaicinoids, including capsaicin, may be self-administered by the user and provide relief from symptoms. Previously it has not been possible to deliver an effective concentration of capsicum intranasally without causing such discomfort to the user requiring the use of an adjunct to desensitize the nasal membranes in order to administer the capsicum. What is needed in the industry is a composition comprising capsicum/capsaicin that is effective in relieving symptoms, but can be used without causing discomfort to the user or requiring adjunct agents.
Applicant is not aware of any prior studies investigating the immediate or short-term relief of symptoms provided by the intranasal administration of capsicum as disclosed in the present application. In addition, Applicant is not aware of any prior studies disclosing that a low homeopathic dilution of capsicum is clinically effective for the treatment of rhinitis.
What is needed in the industry is a nasally administered composition that provides a rapid onset of relief for rhinitis subjects. What is needed in the industry is an intranasally administered composition having a rapid onset of action and significant reduction of symptoms, that is an attractive mono-therapy or adjunctive therapy for the management of rhinitis symptoms, including, but not limited to, chronic rhinitis symptoms. What is needed in the industry is an intranasally administered composition having a quick onset of action with an average time to first relief in less than thirty minutes, less than five minutes, and even less than one minute.
Currently available over the counter (“OTC”) medicated nasal sprays for the relief of rhinitis symptoms necessarily contain labels with a warning indicating that the product should not be used for more than three days. Extended use of these known products leads to the occurrence of rebound congestion and the potential for addiction. These known OTC products are not suitable for use by those with symptoms that last longer than three days, including those suffering chronic conditions, and those suffering from chronic rhinitis symptoms.
What is needed in the industry is an intranasally administered composition that is well-tolerated with prolonged treatment results and with substantially no alteration or impairment in olfaction. What is needed in the industry is an intranasal composition wherein users experience little to no rebound congestion. What is needed in the industry is an intranasal composition wherein use of the composition results in an improvement in olfaction versus placebo after continued use.
What is needed in the industry is an intranasally administered composition wherein during a treatment period is significantly effective at improving nasal congestion, sinus pressure, sinus pain and headache compared to placebo. What is needed in the industry is a nasally administered composition that provides safe, sustained relief over the course of a treatment period. What is needed in the industry is a nasally administered composition that works fast and is safe.
What is needed in the industry is an intranasally administered composition that provides relief from at least one of nasal congestion, sinus pressure and sinus pain with an improved therapeutic response that continues over time with nasal congestion, sinus pressure, sinus pain and headache significantly improved at about 5, 10, 15 and 30 minutes and persists for nasal congestion and sinus pain through the longest time point measured.